Abstract
In humans and FVB/N mice, loss of functional tetraspanin CD151 is associated with glomerular disease characterised by early onset proteinuria and ultrastructural thickening and splitting of the glomerular basement membrane (GBM). To gain insight into the molecular mechanisms associated with disease development, we characterised the glomerular gene expression profile at an early stage of disease progression in FVB/N Cd151−/− mice compared to Cd151+/+ controls. This study identified 72 up-regulated and 183 down-regulated genes in FVB/N Cd151−/− compared to Cd151+/+ glomeruli (p < 0.05). Further analysis highlighted induction of the matrix metalloprotease MMP-10 and the extracellular matrix protein mindin (encoded by Spon2) in the diseased FVB/N Cd151−/− GBM that did not occur in the C57BL/6 diseased-resistant strain. Interestingly, mindin was also detected in urinary samples of FVB/N Cd151−/− mice, underlining its potential value as a biomarker for glomerular diseases associated with GBM alterations. Gene set enrichment and pathway analysis of the microarray dataset showed enrichment in axon guidance and actin cytoskeleton signalling pathways as well as activation of inflammatory pathways. Given the known function of mindin, its early expression in the diseased GBM could represent a trigger of both further podocyte cytoskeletal changes and inflammation, thereby playing a key role in the mechanisms of disease progression.
Highlights
Glomerular diseases are characterised by proteinuria due to damage of the glomerular filtration barrier, initiated either by an intrinsic genetic defect or as a consequence of an underlying systemic disease
We have shown previously that FVB/N Cd151−/− mice present with proteinuria associated with glomerular basement membrane (GBM) damage shortly after birth, which becomes more severe at 3 weeks of age and is associated with some degree of effacement of podocyte foot processes, whereas glomerulosclerosis develops later in the course of the disease
We investigated the expression of genes encoding matrix metalloproteinases (MMPs) in our microarray results since MMPs are crucial in ECM homeostasis and turnover and they have been implicated in the pathology of many glomerular diseases including Alport syndrome[25,26,27]
Summary
Glomerular diseases are characterised by proteinuria due to damage of the glomerular filtration barrier, initiated either by an intrinsic genetic defect or as a consequence of an underlying systemic disease. In order to better understand the mechanisms involved in the tight regulation of the structure and function of the glomerular filtration barrier and potentially identify novel intervention points to prevent or slow glomerular disease progression, we further characterised the early gene expression changes associated with glomerular defect in 3-week-old FVB/N Cd151−/− mice. At this age, GBM maturation in wild type mice is complete and GBM and podocyte ultrastructural defects are evident in FVB/N Cd151−/− kidneys, whilst secondary changes such as glomerulosclerosis and inflammation are not yet prominent[4]. Given the known cellular function of mindin, we propose that early mindin expression might be involved in triggering both further podocyte cytoskeletal changes and an inflammatory response, playing a key role in the early mechanisms of glomerular disease progression
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